The efficacy of mizoribine for the treatment of rheumatoid arthritis and its correlation with renal function.

OBJECTIVES: To evaluate the correlation between the efficacy of mizoribine (MZR) and the factors that might effect MZR concentration: renal function and dosage and administration of MZR in patients with rheumatoid arthritis (RA). METHODS: The efficacy of MZR treatment was prospectively evaluated in 97 RA regardless of dosage, at the 14 participated institutions. The Disease Activity Score 28-CRP3 was used to assess RA activity. The renal function was evaluated based on the serum creatinine and serum cystatin-C (Cys-C). The patients were followed up for 24 weeks. RESULTS: The patients with a mean age 66.2 years included 18 male. The renal function assessment showed increased creatinine in 16.4% of patients and increased Cys-C in 54.5%, suggesting the higher sensitivity of Cys-C to detect impaired renal function than creatinine. In patients with good or moderate response according to the European League against Rheumatism classification criteria, the Cys-C was significantly higher compared with those with no response. MZR treatment was significantly more effective in patients with an arithmetic product of the single MZR dose used and Cys-C of 179 or more. CONCLUSIONS: The efficacy of MZR may increase in proportion to its single dose, or increased Cys-C level in patients with impaired renal function.

Rapidly progressive respiratory failure in mixed connective tissue disease: report of an autopsy case.

A 64-year-old woman presented with exertional dyspnea. The case was diagnosed as mixed connective tissue disease (MCTD) due to presence of swollen fingers, Raynaud's phenomenon, muscle weakness, positive anti-U1RNP antibody, pericarditis and interstitial pneumonia. Although the histology from a transbronchial lung biopsy (TBLB) indicated organizing pneumonia, corticosteroid therapy was postponed for two months at the patient's request. She died 8 weeks later from acute progressive interstitial pneumonia in spite of the administration of intravenous cyclophosphamide combined with prednisolone. The autopsy revealed exudative and organizing diffuse alveolar damage (DAD). Previous reports have shown that DAD is an extremely rare pulmonary complication in MCTD. This report presents a case of MCTD with acute respiratory failure. This case thus suggests that this therapy should be administered as soon as possible.

A case of IgG4-related disease with features of Mikulicz's disease, and retroperitoneal fibrosis and lymphadenopathy mimicking Castleman's disease.

A 51-year-old man developed painless enlargement of the bilateral submandibular and lacrimal glands without xerostomia or xerophthalmia in the absence of autoantibodies to SS-A (Ro) and SS-B (La). In a few years, he developed generalized lymphadenopathy, with markedly elevated serum IgG4, and a computed tomography scan revealed soft-tissue-density lesions around the abdominal aorta, a finding consistent with retroperitoneal fibrosis. Biopsy of the cervical lymph node showed an expansion of the interfollicular area by heavily infiltrating plasma cells, consistent with multicentric Castleman's disease. Immunohistochemical analysis revealed that the IgG4-positive/IgG-positive plasma cell ratio was 80%, leading us to a single diagnosis of IgG4-related disease. High-dose corticosteroid treatment resulted in prompt resolution of the physical, serological, and imaging abnormalities. Although IgG4-related disease can mimic multicentric Castleman's disease, as in our patient, the two diseases have effective but distinct treatments, and thus measurement of serum IgG4 levels and specific immunohistochemical analysis for determining the IgG4-positive/IgG-positive plasma cell ratio are recommended if IgG4-related disease is suspected.

[A rare case of primary Sjögren's syndrome complicated by secondary lymphoid interstitial pneumonia].

A 61-year-old woman was referred to our hospital because of an abnormal chest X-ray shadow. She was diagnosed as having primary Sjögren's syndrome based on sicca syndrome, polyclonal hyper-gamma-globulinemia, and positive results for anti-Ro/SS-A and anti-La/SS-B antibodies. Her chest CT scan revealed bilateral ground-glass shadows and septal thickning in the lower lung field (Fig. 2a). Biopsy specimens obtained by video-assisted thoracoscopy (VATS) showed a dense interstitial lymphoid infiltrate, including lymphocytes and plasma cells, predominantly in the alveolar septae (Fig. 3, a-c). Malignant lymphoma was excluded on the basis of immunohistopathological studies (Fig. 4). A diagnosis of lymphoid interstitial pneumonia was made according to the 2002 American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification (International Classification). After administration of prednisolone and azathioprin, the ground-glass shadows on the chest CT rapidly improved (Fig. 2b). The clinico-radiologic-pathologic diagnosis based on the VATS procedure and the International Classification is appropriate and effective for treating collagen vascular disease-associated interstitial lung disease.

[A case report of segmental arterial mediolysis].

We report a case of 58-year-old woman with a ruptured dissecting aneurysm of the middle colic artery (MCA). Her initial manifestation was sudden and severe right-sided abdominal pain, followed by hemorrhagic shock and acute anemia. Abdominal CT showed a right retroperitoneal hemorrhage. Emergency catheter angiography and therapeutic coil embolization of the middle colic artery were performed and micro aneurysms were enhanced in the jejunal branch. Immunological tests showed nothing abnormal. Follow-up angiography after 3 months showed that the micro aneurysms had disappeared. The patient was diagnosed as having segmental arterial mediolysis (SAM), because no definitive evidence of atherosclerosis and polyarteritis nodosa were observed. SAM is a rare disease of unknown etiology. The arterial lesions developing in elderly patients are characterized by segmental lysis of the abdominal splanchnic arteries resulting in aneurysms, and acute bleeding in a skip pattern. Multiple aneurysms and abdominal pain due to the rupture of these lesions in SAM resemble the clinical findings in polyarteritis nodosa. Differential diagnosis of the two diseases is important because steroid therapy is not beneficial for SAM.

C4B deficiency associated with membranoproliferative glomerulonephritis.

A 10-year-old girl was noted to have microscopic hematuria and proteinuria in 1986. As her urinary abnormalities were persistent, she underwent a renal biopsy on 4 occasions until 2003. Although the appearances of the renal biopsies were strongly suspicious of systemic lupus erythematosus, she never exhibited specific autoantibodies or distinctive symptoms. She received corticosteroid therapy and the urinary findings responded. The 4th component of complement remained low during the period of the observation. Both genotyping and allotyping analysis revealed complete C4B deficiency. Some case reports have mentioned renal disease associated with C4B deficiency and we consider the nephropathy in this case to be related to the C4B deficiency.

A case of hypomyopathic dermatomyositis associated with rapid progressive interstitial pneumonia resistant to multi-immunosuppressive therapy.

The prognosis of interstitial pneumonia in patients with dermatomyositis is thought to depend on the histologic type and response to therapy. We report a case of hypomyopathic dermatomyositis with rapid development of a fatal interstitial pneumonia. Although the histology of lung biopsy indicated minimal alveolitis, the patient died despite multi-immunosuppressive therapy. The autopsy revealed acute and organizing diffuse alveolar damage. In this case, the lung biopsy taken before the acute deterioration did not predict the patient's poor prognosis. Interstitial pneumonia in patients with amyopathic or hypomyopathic dermatomyositis would develop rapidly progressive and refractory. We need larger and better prospective studies to determine whether early and intensive immunosuppressive therapy improves the prognosis of interstitial pneumonia in patients with amyopathic or hypomyopathic dermatomyositis.

[A case of airway-limiting type relapsing polychondritis].

A 59-year-old woman was referred to our hospital for chronic cough and myalgia. Polymyalgia rheumatica (PMR) and bronchial asthma were first diagnosed, and she was prescribed 15 mg/day prednisolone. PMR improved immediately. However, her chronic cough continued, and wheezing was heard on chest auscultation. The flow-volume loop showed a severe expiratory flow limitation and a notching sign at early expiration. Diffuse thickening and narrowing at the trachea and bilateral main bronchus were shown on chest CT. On flexible bronchoscope the trachea and bilateral main bronchus collapsed on expiration. We suspected relapsing polychondritis (RP), but she had no findings of saddle nose or deformity of the external ear. Therefore, biopsy of the tracheal cartilage was done. RP was diagnosed by the modified criteria of Damiani and the histology confirmed degeneration of the tracheal cartilage. She was treated by high dose corticosteroids, and her symptoms improved. This case report emphasizes the need to consider the possibility of RP as a cause of chronic cough or intractable asthma.

Antisynthetase syndrome associated with sarcoidosis.

A 30-year-old man complained of polyarthralgia and fatigue. The clinical findings and laboratory data included myositis, polyarthritis, interstitial pneumonia, Raynaud's phenomenon, mechanic's hand, and anti PL-7 antibody (threonyl-tRNA synthetase antibody). All of these signs were consistent with antisynthetase syndrome. His chest radiograph revealed bilateral hilar lymphadenopathy. Biopsy specimens from his mediastinal lymph node and muscle showed noncaseating epithelioid cell granulomas. Lung histology revealed nonspecific interstitial pneumonia. Antisynthetase syndrome associated with sarcoidosis was diagnosed. Interstitial pneumonia in this patient responded well to high-dose corticosteroid therapy.

[Appearance of central nervous system lupus during corticosteroid therapy and warfarinization in a patient with pure red cell aplasia and antiphospholipid syndrome].

A 48-year-old woman presented to our hospital with epigastralgia and erythema on the left dorsalis pedis. Her medical history included deep venous thrombosis three months prior to admission to our hospital. Upon admission it was determined that she had severe anemia (hemoglobin level 4.6 g/dl). Bone marrow analysis indicated a markedly decreased number of erythroid progenitor cells. A skin biopsy specimen of the erythema revealed microthrombus. Anticardiolipin-beta2GPI antibody and lupus anticoagulant were positive. The patient was diagnosed with pure red cell aplasia (PRCA) and antiphospholipid syndrome (APS). After steroid pulse therapy and warfarinization, her anemia and purpura improved. Three months later she developed depression with positive anti-ribosomal P protein antibody that was indicative of central nervous system lupus. Although her psychometric condition did not respond to steroid pulse therapy, improvement was seen after she received three courses of cyclophosphamide pulse therapy. We report a rare case of CNS lupus that developed during corticosteroid therapy and warfarinization in a patient with PRCA and APS.

Relative transcriptional activities of SAA1 promoters polymorphic at position -13(T/C): potential association between increased transcription and amyloidosis.

The risk associated with the serum amyloid A (SAA) 1 gene and developing AA-amyloidosis is still controversial. In familial Mediterranean fever or Caucasoid rheumatoid arthritis (RA), the SAA1.1 allele is a risk factor for the development of AA-amyloidosis. However, individuals with the SAA1.3 allele are susceptible to AA-amyloidosis in the Japanese RA population, but those with the SAA1.1 are not. Previous reports have indicated that the -13T/C single nucleotide polymorphism (SNP) at the 5'-flanking region of SAA1 appears to be a better marker of AA-amyloidosis than the exon-3 based haplotype, i.e., SAA1.1 or SAA1.3, in both Japanese and American Caucasian populations. So far, it is unknown why the -13T SNP increases the amyloidogenicity of the patients. In the present study, a luciferase reporter gene assay showed that the transcriptional activity of the SAA1 having the -13T-containing promoter was significantly higher than activities of those with -13C-containing promoters (Fisher's protected least significance difference test). We suggest that having the -13T SNP in the SAA1 promoter correlates with the amyloidogenicity in part as a result of this increased transcriptional activity.

Churg-Strauss syndrome associated with hypersensitivity to acetaminophen.

Acetaminophen is a widely used antipyretic drug. We describe a 64-year-old Japanese woman who developed typical Churg-Strauss syndrome after frequent use of acetaminophen. Following the ingestion of acetaminophen, she exhibited various allergic reactions such as asthmatic attacks, pyrexia and petechiae on legs. In the lymphocyte transformation test, a positive reaction to acetaminophen was detected. A muscle biopsy revealed massive extravascular eosinophil infiltration and a necrotizing vasculitis. Hypersensitivity to acetaminophen may be implicated in the development of Churg-Strauss syndrome in this case.

CXCL12 signaling is independent of Jak2 and Jak3.

Janus kinases (Jaks) are a small family of cytoplasmic tyrosine kinases, critical for signaling by Type I and II cytokine receptors. The importance of Jaks in signaling by these receptors has been firmly established by analysis of mutant cell lines, the generation of Jak knock-out mice, and the identification of patients with Jak3 mutations. While a number of other ligands that do not bind Type I and II cytokine receptors have also been reported to activate Jaks, the requirement for Jaks in signaling by these receptors is less clear. Chemokines for example, which bind seven transmembrane receptors, have been reported to activate Jaks, and principally through the use of pharmacological inhibitors, it has been argued that Jaks are essential for chemokine signaling. In the present study, we focused on CXCR4, which binds the chemokine CXCL12 or stromal cell-derived factor-1, a chemokine that has been reported to activate Jak2 and Jak3. We found that the lack of Jak3 had no effect on CXCL12 signaling or chemotaxis nor did overexpression of wild-type versions of the kinase. Similarly, overexpression of wild-type or catalytically inactive Jak2 or "knocking-down" Jak2 expression using siRNA also had no effect. We also found that in primary lymphocytes, CXCL12 did not induce appreciable phosphorylation of any of the Jaks compared with cytokines for which these kinases are required. Additionally, little or no Stat (signal transducer and activator of transcription) phosphorylation was detected. Thus, we conclude that in contrast to previous reports, Jaks, especially Jak3, are unlikely to play an essential role in chemokine signaling.

The biology of IL-12: coordinating innate and adaptive immune responses.

Cytokines play critical roles in regulating all aspects of immune responses, including lymphoid development, homeostasis, differentiation, tolerance and memory. Interleukin (IL)-12 is especially important because its expression during infection regulates innate responses and determines the type and duration of adaptive immune response. IL-12 induces interferon-gamma (IFN-gamma) production by NK, T cells, dendritic cells (DC), and macrophages. IL-12 also promotes the differentiation of naïve CD4+ T cells into T helper 1 (Th1) cells that produce IFN-gamma and aid in cell-mediated immunity. As IL-12 is induced by microbial products and regulates the development of adaptive immune cells, IL-12 plays a central role in coordinating innate and adaptive immunity. IL-12 and the recently identified cytokines, IL-23 and IL-27, define a family of related cytokines that induce IFN-gamma production and promote T cell expansion and proliferation.